1. Field of the Invention
This invention relates to 2',3'-dideoxy-2'-fluoronucleosides and 2',3'-dideoxy-2',3-didehydro-2'-fluoronucleosides, their preparation, and their use in HIV infection.
2. Background - Related References
Marquez et al., Biochem. Pharmacol., 36 (17), 2719-2722 (1987) disclose two 2'-F-substituted dideoxynucleoside derivatives of dideoxyadenosine (ddA; compound (A)) which constitute acid stable, active anti-HIV agents. These two compounds are shown below and designated compound B [6-amino-(.beta.'D-2',3'-dideoxy-2'-fluororibofuranosyl)-9-H-purine; 2'-F-ddA] and compound C [6-amino-9-(.beta.-D-2',3'-dideoxy-2'-fluoroarabinofuranosyl)-H-purine; 2'-F-ara-ddA]. ##STR1##
Compound B was obtained from 3'-deoxy-ara-A (compound D) in four steps which involved protection of the 5'-hydroxyl group with dimethoxytrityl chloride, activation of the 2'-hydroxyl group via formation of the corresponding triflate, inversion of configuration at the 2'-position by an SN.sub.2 displacement using tetra-n-butylammonium fluoride, and removal of the dimethoxytrityl protective group using dichloracetic acid.
Compound C was prepared by condensing 6-chloropurine with 3-O-acetyl-5-O-benzyl-2-deoxy-2-fluoro-D-arabinofuranosyl bromide, separating the expected four isomers and characterizing the correct 6-chloro isomer, and subjecting the correct isomer to ammonolysis with concentrated methanolic ammonia to give Compound E, 6-amino-9-(.beta.-D-2'deoxy-2'-fluoroarabinofuranosyl)-9H-purine (2'F-ara-dA; compound E). Selective protection of the 5'-hydroxyl function of Compound E with t-butyldimethylsilyl chloride gave a product that permitted the 2-step reduction of the 3'-hydroxy group. Treatment with phenyl chlorothionocarbonate, followed by reduction of the intermediate 3'-O-phenoxythiocarbonyl derivative with tri-n-butyl tin hydride, produced the desired 2',3'-dideoxynucleoside. Removal of the 5'-blocking group with tetra-n-butyl ammonium fluoride gave 2'-F-ara-ddA (compound C).
The results of biological testing showed that Compound C having stereochemistry of fluorine at the 2'-position in the .beta. ("up") configuration provided a compound about as active and potent as AZT or ddA against HIV. Compound B having fluoride at the 2'-position in the .alpha. ("down") configuration gave dramatically different activity, being protective against HIV to 13% of that protection seen with ddA and was more toxic than ddA.
U.S. Ser. No. 028817 filed Mar. 20, 1987, cross-referenced above, discloses a process for producing 2',3'-dideoxynucleosides represented by the formula. ##STR2##
The process for producing two representative dideoxynucleoside according to U.S. Ser. No. 028817 is outlined in Scheme I below. ##STR3##
Brundidge et al., U.S. Pat. No. 4,625,020, discloses a process for producing 1-halo-2-deoxy-2-fluoroarabinofuranoside derivatives (Compound of Formula F), bearing protective ester groups, from 1,3,5-tri-O-acyl-ribofuranose. The 1-halo derivatives are intermediates in the synthesis of therapeutically active nucleosidic compounds (compound of Formula G). ##STR4##
Lopez et al., EP Patent App. Publication No. 0,010,205 discloses 5-substituted 1-(2'-deoxy-2'-substituted-beta-D-arabinofuranosyl)pyrimidine nucleosides wherein the 2'-substituent, X, is halogen, alkylsulfonyl or arylsulfonyl (compound of Formula H). ##STR5##